The mouse model of experimental skin carcinogenesis has long proposed that epidermal stem cells are a major target of carcinogens and form the latent neoplastic population that ultimately expands into tumors. We have provided experimental evidence of this using the CD34 knockout (CD34KO) mouse, based on the hypothesis that CD34, which is uniquely expressed on hair follicle stem cells, plays a dynamic role in mediating stem cell response to carcinogens. CD34KO mice exhibit a striking impairment in skin tumor development and we have linked this phenotype to aberrant tumor promoter-induced activation of hair follicle cycling and stem cell proliferation. Further, we have evidence suggesting that hair follicle stem cells lacking CD34 have a reduced proliferative potential, based upon cell cycle analysis and growth in clonogenic culture, demonstrating that CD34 is critical for stem cell responsiveness as well underscoring the contribution of hair follicle stem cell contribution to tumor development. Our laboratory was the first to demonstrate that CD34 is expressed on mouse hair follicle stem cells, and through this, we developed methodology that facilitated enrichment for living stem cells. Microarray and proteomic analysis of CD34-expressing stem cells from both untreated and TPA-treated mice has yielded valuable insights into how stem cells respond to chemical exposure and have highlighted several novel genes, including Tbx1 and Stathmin. We have shown that a squamous cell carcinoma cell line transfected with mouse Tbx1 have reduced growth in culture, fail to form colonies in soft agar, and have reduced tumor growth in vivo, implicating a role for Tbx1 in tumor growth and development. Further, we have data suggesting that Tbx1 may play a role in DNA repair through interaction with p53 and Mre11. Stathmin is a well described modulator of cell cycle, but has not been shown in human or mouse skin and skin tumors. Our evidence suggests a high level of expression in actively growing hair follicles, in BCC and SCC of human origin, and SCC of mouse origin. Additionally, stathmin appears to be upregulated in the hair follicle stem cells after TPA treatment, and therefore may be an early indicator of stem cells activation. Taken together, these studies are providing unique insight into stem cell response to environmental exposures, which may lead to novel targets for intervention and prevention of skin cancers in humans.